Benzothieno[3,2-c]pyridines as α2 antagonists

ABSTRACT

The present invention concerns the compounds of formula                    
     the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein each R 1  is independently hydrogen, halogen, C 1-6 alkyl, nitro, hydroxy or C 1-4 alkyloxy; Alk is C 1-6 alkanediyl; n is 1 or 2; p is 0, 1 or 2; D is an optionally substituted mono-, bi- or tricyclic nitrogen containing heterocycle having central α 2 -adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. §371 ofPCT/EP99/07418 filed Oct. 1, 1999, which claims priority from EP98.203.363.1, filed Oct. 6, 1998.

The present invention concerns benzothieno[3,2-c]pyridine derivativeshaving central α₂-adrenoceptor antagonist activity. It further relatesto their preparation, compositions comprising them and their use as amedicine.

Central α₂-adrenoceptor antagonists are known to increase noradrenalinerelease by blocking presynaptic α₂-receptors which exert an inhibitingcontrol over the release of the neurotransmitter. By increasing thenoradrenaline concentrations, α₂-antagonists can be used clinically forthe treatment or prophylaxis of depression, cognitive disturbances,Parkinson's disease, diabetes mellitus, sexual dysfunction andimpotence, elevated intraocular pressure, and diseases related todisturbed enterokinesia, since all these conditions are associated witha deficiency of noradrenaline in the central or peripheral nervoussystem.

The compounds of the present invention are novel and have a specific andselective binding affinity for the different known subtypes of theα₂-adrenoceptors, i.e. the α_(2A), α₂B and α_(2C)-adrenoceptor.

The present invention concerns the compounds of formula

the N-oxide forms, the pharmaceutically acceptable addition salts andthe stereochemically isomeric forms thereof, wherein:

each R¹ is independently hydrogen, halogen, C₁₋₆alkyl, nitro, hydroxy or

C₁₋₄alkyloxy;

Alk is C₁₋₆alkanediyl;

n is 1 or 2;

p is 0, 1 or2;

D is 1- or 2-benzimidazolyl, 2(3H)benzoxazolone-3-yl or a radical offormula

wherein

each X independently represents O, S or NR¹²;

R² is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl;

R³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino or mono-or

di(C₁₋₆alkyl)amino;

R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹ and R¹² each independently are hydrogen orC₁₋₆alkyl;

R⁹ is hydrogen, C₁₋₆alkyl or aryl; or

R³ and R⁴ taken together may form a bivalent radical —R³—R⁴— of formula

—CH₂—CH₂—CH₂— (a-1); —CH₂—CH₂—CH₂—CH₂— (a-2); —CH=CH—CH₂— (a-3);—CH₂—CH=CH— (a-4) or —CH=CH—CH=CH— (a-5);

wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) eachindependently may be replaced by halo, C₁₋₆alkyl, arylC₁₋₆alkyl,trifluoromethyl, amino, hydroxy, C₁₋₆alkyloxy or C₁₋₁₀alkylcarbonyloxy;or where possible, two germinal hydrogen atoms may be replaced byC₁₋₆alkylidene or arylC₁₋₆alkylidene; or

—R³—R⁴— may also be

—S—CH₂—CH₂— (a-6); —S—CH₂—CH₂—CH₂— (a-7); —S—CH=CH— (a-8); —NH—CH₂—CH₂—(a-9); —NH—CH₂—CH₂—CH₂— (a-10); —NH—CH=CH— (a-11); —NH—CH=N— (a-12);—S—CH=N— (a-13) or —CH=CH—O— (a-14);

wherein one or where possible two or three hydrogen atoms in saidradicals (a-6) to (a-14) each independently may be replaced by C₁₋₆alkylor aryl; and

aryl is phenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, nitro, cyano, trifluoromethyl, C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- anddi(C₁₋₆alkyl)amino, carboxyl, C₁₋₆alkyloxycarbonyl andC₁₋₆alkylcarbonyl.

As used in the foregoing definitions the term halogen is generic tofluoro, chloro, bromo and iodo. The term C₁₋₆alkyl defines straight andbranched saturated hydro-carbons, having from 1 to 6 carbon atoms suchas, for example, methyl, ethyl, propyl, butyl, 1-methylethyl,1,1-dimethylethyl, 2-methylpropyl, pentyl, hexyl and the like. The termC₁₋₁₀alkyl is meant to include C₁₋₆alkyl radicals and the higherhomologues thereof having 7 to 10 carbon atoms such as, for example,heptyl, octyl, nonyl, decyl and the like. The term C₁₋₆alkanediyldefines bivalent straight or branch chained alkanediyl radicals havingfrom 1 to 6 carbon atoms such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the like; the term C₁₋₆alkylidene defines bivalentstraight or branch chained alkylidene radicals having from 1 to 6 carbonatoms such as, for example, methylene, ethylidene, 1-propylidene,1-butylidene, 1-pentylidene, 1-hexylidene and the like.

The addition salts as mentioned herein are meant to comprise thetherapeutically active addition salt forms which the compounds offormula (I) are able to form with appropriate acids, such as, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and thelike acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare also meant to comprise the therapeutically active non-toxic base, inparticular, a metal or amine addition salt forms which the compounds offormula (I) are able to form. Said salts can conveniently be obtained bytreating the compounds of formula (I) containing acidic hydrogen atomswith appropriate organic and inorganic bases such as, for example, theammonium salts, the alkali and earth alkaline metal salts, e.g. thelithium, sodium, potassium, magnesium, calcium salts and the like, saltswith organic bases, e.g. the benzathine, N-methyl-D-glucamine,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like. Conversely said salt forms can beconverted by treatment with an appropriate base or acid into the freeacid or base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) are able to form and said solvatesare meant to be included within the scope of the present invention.Examples of such solvates are, e.g. the hydrates, alcoholates and thelike.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

The term stereochemically isomeric forms as used herein defines all thepossible isomeric forms in which the compounds of formula (I) may occur.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term compounds of formula (I) is meant toinclude also the N-oxide forms, the pharmaceutically acceptable additionsalts and all stereoisomeric forms.

Suitably, aryl is phenyl or phenyl substituted halo or C₁₋₆alkyl.

A special group of compounds are those compounds of formula (I) whereinp is 0.

An interesting group of compounds are those compounds of formula (I)wherein n is 1 and R¹ is hydrogen, chloro, fluoro, methyl, methoxy ornitro, in particular R¹ is hydrogen or chloro; or, wherein n is 2 andboth R¹ are methoxy. Preferred positions for R¹ are position 7 and 8 asdepicted below.

Another interesting group of compounds are those compounds of formula(I) wherein Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl,1,4-butanediyl or 1,5-pentanediyl, in particular 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, more in particular 1,2-ethanediyl.

Still another interesting group of compounds are those compounds offormula (I) wherein D is a radical of formula (a), (b), (c), (d) or (f).

Particular compounds are those compounds of formula (I) wherein D is aradical of formula (a) wherein R² is C₁₋₆alkyl, aryl or arylC₁₋₆alkyl,and R³ and R⁴ form a bivalent radical of formula —R³—R⁴—, and suitably—R³—R⁴— is a radical of formula (a-5) or (a-8); or D is a radical offormula (b) wherein R⁵ and R⁶ are C₁₋₆alkyl; or D is a radical offormula (c) wherein R⁷ is hydrogen; or D is a radical of formula (d)wherein R⁸ is hydrogen; or D is a radical of formula (f) wherein R¹⁰ ishydrogen and X is O or S, in particular S.

Preferred compounds are those compounds of formula (I) wherein n is 1and R¹ is hydrogen or chloro, p is 0, Alk is 1,2-ethanediyl and D is aradical of formula (a), (b), (c), (d) or (f).

Most preferred compounds are the compounds depicted below or theirN-oxide forms, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof:

The compounds of formula (I) can generally be prepared by N-alkylating abenzo-thieno[3,2-c]pyridine derivative of formula (II) with analkylating reagent of formula (III) following the procedure described inEP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.Conveniently, both intermediates are reacted in a suitable solvent suchas, for example, methylisobutyl keton, in the presence of a base suchas, for example, sodium carbonate, and optionally in the presence of acatalyst such as, for example, potassium iodide.

In intermediate (III), W¹ represents an appropriate reactive leavinggroup such as, for example, halo, e.g. chloro, bromo or iodo;sulfonyloxy, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy.

In this and the following reactions, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such asextraction, crystallization, trituration and chromatography.

The compounds of formula (I) wherein D is a radical of formula (e),being represented by formula (I-e), may be prepared by deprotecting aN-protected intermediate of formula (IV) wherein P is a protective groupsuch as, for example, a C₁₋₄alkyloxy-carbonyl group, and subsequentlyN-acylating the resulting intermediate with an acyl derivative offormula (V) wherein W² is an appropriate reactive leaving group such as,for example, a halogen. The reaction may be performed in a suitablesolvent such as, for example, chloroform, methylisobutyl keton or analcohol, in the presence of a base such as, for example, sodiumcarbonate.

The compounds of formula (I) wherein D is a radical of formula (f),being represented by formula (I-f), can be prepared by N-alkylating anamine of formula (VI) with an intermediate of formula (VII) wherein W³is an appropriate reactive leaving group such as, for example, ahalogen.

The compounds of formula (I) may be converted into each other followingart-known functional group transformation reactions.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

A number of intermediates and starting materials are commerciallyavailable or are known compounds which may be prepared according toart-known methodologies.

For example, some of the intermediates of formula (III) and theirpreparations are described in EP-A-0,037,265, EP-A-0,070,053 ,EP-A-0,196,132 and in EP-A-0,378,255.

Intermediates of formula (II) wherein X is S can be prepared analogousto the procedure described in Capps et al. (J. Am. Chem. Soc., 1953, p.697) or U.S. Pat. No. 3,752,820.

A particular synthesis route for the preparation of intermediates offormula (II) is depicted in scheme 1.

Step a can be performed analogous to the procedure described inTetrahedron (1981), 37, p 979-982. Benzofurans resulting from step chave been used as intermediates in U.S. Pat. No. 4,210,655. The furtherreaction steps are analogous to the reaction procedures described inU.S. Pat. No. 3,752,820.

Alternatively, intermediates of formula (II) can be prepared using thereaction steps depicted in scheme 2.

Step a can be performed analogous to the procedure described inHeterocycles (1994), 39(1), p. 371-380. Step b can be performedanalogous to the procedure described in J. Med. Chem. (1986), 29(9), p.1643-1650. Further reaction steps can be performed analogous to the onesdescribed in J. Heterocycl. Chem. (1979), 16, p. 1321.

Some of the compounds of formula (I) and some of the intermediates inthe present invention contain at least one asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers.

Pure stereochemically isomeric forms of the compounds of formula (I) mayalso be obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically. The pure and mixedstereochemically isomeric forms of the compounds of formula (I) areintended to be embraced within the scope of the present invention.

The compounds of formula (I), the N-oxides, the pharmaceuticallyacceptable addition salts and stereochemically isomeric forms thereof,block the presynaptic α₂-receptors on central noradrenergic neurons thusincreasing the noradrenaline release. Blocking said receptors willsuppress or relieve a variety of symptoms associated with a deficiencyof noradrenaline in the central or peripheral nervous system.Therapeutic indications for using the present compounds are depression,cognitive disturbances, Parkinson's disease, diabetes mellitus, sexualdysfunction and impotence and elevated intraocular pressure.

Blocking α₂ receptors in the central nervous system has also been shownto enhance the release of serotonine which may add to the therapeuticaction in depression (Maura et al., 1992, Naunyn-Schmiedeberg's Arch.Pharmacol., 345: 410-416).

It has also been shown that blocking α₂ receptors may induce an increaseof extracellular DOPAC (3,4-dihydro-phenylacetic acid) which is ametabolite of dopamine and noradrenaline.

In view of the usefulness of the subject compounds in the treatment ofdiseases associated with a deficiency of noradrenaline in the centralnervous system, in particular depression and Parkinson's disease, thepresent invention provides a method of treating warm-blooded animalssuffering from such diseases, in particular depression and Parkinson'sdisease, said method comprising the systemic administration of antherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable addition salt thereof.

The present compounds are also potentially useful in the treatment ofAlzheimer's disease and dementia as it is known that α₂-antagonistspromote the release of acetylcholine (Tellez et al. 1997, J. Neurochem.68:778-785).

In general it is contemplated that an effective therapeutic daily amountwould be from about 0.01 mg/kg to about 4 mg/kg body weight.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine. Further, the presentinvention also relates to the use of a compound of formula (I) for themanufacture of a medicament for treating depression or Parkinson'sdisease.

Ex vivo as well as in vitro receptor signal-transduction and receptorbinding studies can be used to evaluate the α₂ adrenoceptor antagonismof the present compounds. As indices of central α₂-adrenoceptor blockadein vivo, the reversal of the loss of righting reflex observed in ratsafter intravenous injection of xylazine and inhibition of the tremorsinduced by reserpine in rats can be used.

The compounds of the present invention also have the ability to rapidlypenetrate into the central nervous system.

For administration purposes, the subject compounds may be formulatedinto various pharmaceutical compositions comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound of formula (I). To prepare thepharmaceutical compositions of this invention, an effective amount ofthe particular compound, in addition salt or in free acid or base form,as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable solutions containing compounds of formula (I) maybe formulated in an oil for prolonged action. Appropriate oils for thispurpose are, for example, peanut oil, sesame oil, cottonseed oil, cornoil, soy bean oil, synthetic glycerol esters of long chain fatty acidsand mixtures of these and other oils. Injectable suspensions may also beprepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wettable agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause any significant deleterious effects on theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment. Addition salts of (I) due totheir increased water solubility over the corresponding free base orfree acid form, are obviously more suitable in the preparation ofaqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART Preparation of the Intermediate Compounds Example A1

a) A mixture of 1,2,3,4-tetrahydro[1]benzothieno[3,2-c]pyridine HCl(1:1) (0.02 mol), 1,1-dimethylethyl (4-chlorobutyl)carbamate (0.044mol), Na₂CO₃ (0.05 mol) and KI (catalytic quantity) in4-methyl-2-pentanone (200 ml) was stirred and refluxed overnight, thencooled to room temperature and the solvent was evaporated. The residuewas washed with water and extracted with CH₂Cl₂. The separated organiclayer was dried, filtered and the solvent evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH90/10). The desired fractions were collected and the solvent wasevaporated, yielding 1,1-dimethylethyl[4-(3,4-dihydro[1]benzothieno[3,2-c]pyridine-2(1H)-yl)butyl]carbamate(intern 1).

b) A mixture of intermediate (1) (0.02 mol) in HCl/2-propanol (20 ml)and 2-propanol (150 ml) was stirred and refluxed for 30 min, then cooledto room temperature. The precipitate was filtered off and dried,yielding 4.9 g of3,4-dihydro[1]benzothieno-[3,2-c]pyridine-2(1H)-butanaminedihydrochloride (73%) (interm. 2).

Example A2

a) Butyllithium (2.5 M) (0.27 mol) was added dropwise to6-methoxybenzo[b]-thiophene (0.25 mol) in tetrahydrofuran (1000 ml),stirred at −30° C. The mixture was stirred for 10 min at −30° C.Ethylene oxide (0.38 mol in 100 ml tetrahydrofuran) was added dropwiseat −30° C. The mixture was allowed to warm to room temperature andstirred for 3 hours. The mixture was acidified with dilute HCl solution.The solvent was evaporated. The residue was diluted with water and thismixture was extracted with CH₂Cl₂. The separated organic layer wasdried, filtered and the solvent evaporated. The residue was stirred inhexane, filtered off and dried, yielding 41.3 g of6-methoxybenzo[b]thiophene-2-ethanol (interm. 3).

b) Methanesulfonyl chloride (0.21 mol) was added to a mixture ofintermediate (3) (0.19 mol) and N,N-diethylethanamine (0.21 mol) inCH₂Cl₂ (1 L), stirred at 0° C. The reaction mixture was stirred for 4hours at room temperature, then poured out into water. The separatedorganic layer was dried, filtered and the solvent evaporated. Theresidue was triturated under diisopropyl ether, filtered off and dried,yielding 50.5 g of 6-methoxybenzo[b]thiophene-2-ethanol methanesulfonate(ester) (interm.4).

c) A mixture of intermediate (4) (0.18 mol) and sodiumiodide (0.45 mol)in 2-propanone (1000 ml) was stirred and refluxed for 9 hours, thencooled to room temperature and the solvent was evaporated. The residuewas washed with water and extracted with CH₂Cl₂. The separated organiclayer was dried, filtered and the solvent evaporated, yielding 57 g of2-(2-iodoethyl)-6-methoxybenzo[b]thiophene (interm.5).

d) Intermediate (5) (0.18 mol) was added portionwise to a mixture of1,3,5,7-tetra-azatricyclo[3.3.1.13,7]decane (0.45 mol) in CHCl₃ (600ml). The reaction mixture was stirred and refluxed overnight, thencooled to room temperature. The precipitate was filtered off and dried,yielding 54.2 g of1-[2-(6-methoxybenzo[b]thiophen-2-yl)ethyl]-1,3,5,7-tetraazatricyclo[5.1.1.1-5,7]decaniumiodide (interm.6).

e) A mixture of intermediate (6) (0.12 mol) and HCl (0.50 mol) inethanol (171 ml) was stirred for 2 days at room temperature. More HCl(10 ml) and ethanol (40 ml) were added and the reaction mixture wasstirred and refluxed for one hour, then cooled to room temperature. Thesolvent was evaporated. The residue was stirred in 2-propanol, thenfiltered off. The solid was dried and reconverted into the free basewith 20% NaOH. The separated organic layer was dried, filtered and thesolvent evaporated. The residue was dissolved in 2-propanol andconverted into the hydrochloric acid salt (1:1) with HCl/2-propanol. Theprecipitate was filtered off and dried, yielding 13.1 g of1,2,3,4-tetrahydro-7-methoxy[1]benzothieno[3,2-c]pyridine (50%)(interm.7). In an analogous way were also prepared:

1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[3,2-c]pyridinehydrochloride(1:1) (interm.8); and

1,2,3,4-tetrahydro-8-fluoro-[1]benzothieno[3,2-c]pyridinehydrochloride(1:1) (interm. 9).

Preparation of the Compounds of Formula (I) Example B1

A mixture of 1,2,3,4-tetrahydro-benzothieno[3,2-c]pyridine [preparedanalogous to the procedure described in J. Am. Chem. Soc., 1953, p. 697](0.009 mol), 3-(2-chloro-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(0.011 mol), Na₂CO₃ (0.023 mol) and KI (catalytic quantity) inmethylisobutyl keton (100 ml) was stirred and refluxed overnight, thencooled to room temperature and the solvent was evaporated. The residuewas washed with water and extracted with CH₂Cl₂. The separated organiclayer was dried, filtered and the solvent evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH90/10). The desired fractions were collected and the solvent wasevaporated. The residue was converted into the (E)-2-butenedioic acidsalt (2:1). The precipitate was filtered off and dried, yielding 2.3 g(47%) of3-[2-(3,4-dihydro-[1]benzothieno[3,2-c]pyridin-2(1H)-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(E)-2-butenedioate(2:1) (comp. 1).

Example B2

Na₂CO₃ (0.100 g) was added to a solution of1,2,3,4-tetrahydro-benzothieno[3,2-c]-pyridine (0.00044 mol) and3-(4-chlorobutyl)-2,4(1H,3H)quinazolinedione (0.100 g) in methylisobutylketon (2 ml) and the resulting reaction mixture was stirred overnight at100° C. The desired compound was isolated and purified by HPLC overKromasil Spherical underivated silica gel (eluent: CH₂Cl₂/(CH₂Cl₂/CH₃OH90/10)/CH₃OH (0 min) 100/0/0, (10.50 min) 0/100/0, (12.50 min) 50/0/50,(14.00 min) 0/0/100, (15.01-20.00 min) 100/0/0). The pure fractions werecollected and the solvent was evaporated, yielding 0.025 g of3-[4-(3,4-dihydro-[1]benzothieno[3,2-c]pyridin-2(1H)-yl)butyl]-1,3-quinazoline-2,4(1H,3H)-dione(comp. 6).

Example B3

A mixture of intermediate (2) (0.01 mol), 2-chlorobenzothiazole (0.012mol) and Na₂CO₃ (0.015 mol) in 2 ethoxy ethanol (50 ml) was stirred andrefluxed overnight. The reaction mixture was filtered hot and thefiltrate was allowed to cool to room temperature. The solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 90/10). The desired fractions werecollected and the solvent was evaporated. The residue was converted intothe hydrochloric acid salt (1:2). The precipitate was filtered off anddried, yielding 2.3 g ofN-2-benzothiazolyl-3,4-dihydro[1]benzothieno[3,2-c]pyridine-2(1H)-butanaminedihydrochloride (49%) (comp. 18).

Table 1 lists compounds of formula (I) which were made analogous to oneof the above examples.

Co. Ex. No. No. R¹ Alk D Salt form  1 B1 H —(CH₂)₂—

(E)-2-butenedioate (2:1)  2 B1 H —(CH₂)₂—

(E)-2-butenedioate (2:1)  3 B1 H —(CH₂)₃—

(E)-2-butenedioate (2:1)  4 B2 H —(CH₂)₃—

—  5 B2 H —(CH₂)₄—

—  6 B2 H —(CH₂)₄—

—  7 B1 8-Cl —(CH₂)₂—

—  8 B1 8-Cl —(CH₂)₂—

(E)-2-butenedioate (2:1)  9 B1 H —(CH₂)₃—

— 10 B1 8-CH₃ —(CH₂)₂—

HCl (1:2), H₂O (1:1) 11 B1 8-CH₃ —(CH₂)₂—

(E)-2-butenedioate (1:1) 12 B1 8-Cl —(CH₂)₃—

(E)-2-butenedioate (2:1) 13 B1 8-F —(CH₂)₂—

— 14 B1 8-F —(CH₂)₂—

— 15 B1 8-F —(CH₂)₃—

(E)-2-butenedioate (2:1) 16 B2 H —(CH₂)₄—

(E)-2-butenedioate (1:1) 17 B2 H —(CH₂)₂—

HCl (1:1) 18 B3 H —(CH₂)₄—

HCl (1:2) 19 B1 H —(CH₂)₂—

HCl (1:2) 20 B1 H —(CH₂)₂—

(E)-2-butenedioate (1:1) 21 B1 7-OCH₃ —(CH₂)₂—

HCl 1:1); H₂O (1:1); (E)-2-butenedioate (2:1) 22 B1 7-OCH₃ —(CH₂)₂—

(E)-2-butenedioate (2:3) H₂O (1:1) 23 B1 7-OCH₃ —(CH₂)₃—

(E)-2-butenedioate (2:3) 24 B1 7-Cl —(CH₂)₂—

HCl (1:2), H₂O (1:1), 2-propanolate (1:1)

C. Pharmacological Examples Example C.1 In vitro Binding Affinity for α₂Receptors

The interaction of the compounds of formula (I) with α₂ receptors wasassessed in in vitro radioligand binding experiments.

In general, a low concentration of a radioligand with a high bindingaffinity for a particular receptor is incubated with a sample of atissue preparation enriched in a particular receptor or with apreparation of cells expressing cloned human receptors in a bufferedmedium. During the incubation, the radioligand binds to the receptor.When equilibrium of binding is reached, the receptor bound radioactivityis separated from the non-bound radioactivity, and the receptor boundactivity is counted. The interaction of the test compounds with thereceptor is assessed in competition binding experiments. Variousconcentrations of the test compound are added to the incubation mixturecontaining the receptor preparation and the radioligand. Binding of theradioligand will be inhibited by the test compound in proportion to itsbinding affinity and its concentration.

The radioligand used for α_(2A), α_(2B) and α_(2C) receptor binding is³H-rauwolscine and the receptor preparation used is the Chinese HamsterOvary (CHO) cell expressing cloned human α_(2A), α_(2B) and α_(2C)receptors.

The compounds exemplified in the experimental part above all had an IC₅₀value (concentration whereby 50% of the receptors is inhibited) for eachof the three receptors of at least 10⁶ M.

D. Composition Examples

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable addition saltor a stereochemically isomeric form thereof.

Example D.1 Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate arevigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, each comprising 20mg of the A.I.

Example D.2 Film-coated Tablets

Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wetpowder mixture is sieved, dried and sieved again. Then there are added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole is mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate,,5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

Example D.3 Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

Example D.4 Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration and filled in sterilecontainers.

What is claimed is:
 1. A compound of formula

a N-oxide form, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein: each R¹ isindependently hydrogen, halogen, C₁₋₆alkyl, nitro, hydroxy orC₁₋₄alkyloxy; Alk is C₁₋₆alkanediyl; n is 1 or2; p is 0, 1 or 2; D is aradical of formula

wherein each X independently represents O, S or NR¹²; R² is hydrogen,C₁₋₆alkyl, aryl or arylC₁₋₆alkyl; R³ is hydrogen, C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylthio, amino or mono- or di(C₁₋₆alkyl)amino; R⁴,R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹ and R¹² each independently are hydrogen orC₁₋₆alkyl; R⁹ is hydrogen, C₁₋₆alkyl or aryl; or R³ and R⁴ takentogether may form a bivalent radical —R³—R⁴— of formula —CH₂—CH₂—CH₂—(a-1); —CH₂—CH₂—CH₂—CH₂— (a-2); —CH=CH—CH₂— (a-3); —CH₂—CH=CH— (a-4); or—CH=CH—CH=CH— (a-5);

wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) eachindependently may be replaced by halo, C₁₋₆alkyl, arylC₁₋₆alkyl,trifluoromethyl, amino, hydroxy, C₁₋₆alkyloxy or C₁₋₁₀alkylcarbonyloxy;or where possible, two geminal hydrogen atoms may be replaced byC₁₋₆alkylidene or arylC₁₋₆alkylidene; or —R³-R⁴-may also be —S—CH₂—CH₂—(a-6); —S—CH₂—CH₂—CH₂— (a-7); —S—CH=CH— (a-8); —NH—CH₂—CH₂— (a-9);—NH—CH₂—CH₂—CH₂— (a-10); —NH—CH=CH— (a-11); —NH—CH=N— (a-12); —S—CH=N—(a-13); or —CH=CH—O— (a-14);

wherein one or where possible two or three hydrogen atoms in saidradicals (a-6) to (a-14) each independently may be replaced by C1-6alkylor aryl; and aryl is phenyl or phenyl substituted with one, two or threesubstituents selected from halo, hydroxy, nitro, cyano, trifluoromethyl,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- anddi(C₁₋₆alkyl)amino, carboxyl, C₁₋₆alkyloxycarbonyl andC₁₋₆alkylcarbonyl.
 2. A compound according to claim 1 wherein D is aradical of formula (a).
 3. A compound selected from the group consistingof: